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The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. SIGNIFICANCE STATEMENT: The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

In 2014, specific recommendations for complement nomenclature were presented by the complement field. There remained some unresolved designations and new areas of ambiguity, and here we propose solutions to resolve these remaining issues. To enable rapid understanding of the intricate complement system and facilitate therapeutic development and application, a uniform nomenclature for cleavage fragments, pattern recognition molecules (PRMs) and enzymes of the lectin pathway and regulatory proteins of the complement system are proposed, and a standardization of language to designate different activation states of complement components is recommended.

Objective: Rituximab (RTX)‐treated patients exhibit suboptimal responses to COVID‐19 vaccines. However, existing research primarily involves patients already receiving RTX when vaccines were introduced, failing to account for the current landscape where patients are vaccinated before initiating RTX. Our objective was to compare the serological response to COVID‐19 vaccines in patients vaccinated before or after RTX initiation. Methods: We included 254 RTX‐treated patients with autoimmune inflammatory rheumatic diseases (AIIRDs) and 113 blood donors (BDs) in a retrospective, observational cohort study. Patients were categorized based on the timing of RTX treatment relative to primary COVID‐19 vaccination. Serological vaccine responses were assessed using three immunoassays, and logistic regression analysis was used to identify predictors of serological response. Results: Patients vaccinated before initiating RTX treatment had significantly higher seroconversion rates of SARS‐CoV‐2 immunoglobulin G (87%) and neutralizing antibodies (91%) compared with those receiving RTX before and after vaccination (n = 132) (61% and 65%, respectively). In the logistic regression analysis, a positive serological response was associated with the number of vaccines administered >9 months after the last RTX treatment. Patients receiving the highest number of vaccines with >9 months after RTX showed a response comparable to that of the BDs. Conclusion: Vaccinating before RTX initiation yields a robust serological response in patients with AIIRDs. Furthermore, we highlight the reversibility of antibody impairment after RTX treatment cessation, provided that adequate vaccinations occur within a minimum of 9 months after RTX. Our findings offer essential insights for clinical decision‐making regarding COVID‐19 vaccination and RTX treatment, alleviating concerns about future RTX use. [ABSTRACT FROM AUTHOR]

Background: Knowledge about SARS-CoV-2 antibody dynamics in neonates and direct comparisons with maternal antibody responses are not well established. This study aimed to characterize and directly compare the maternal and infant antibody response in a national birth cohort from the Faroe Islands. Methods: The levels of immunoglobulins (Ig) targeting the receptor binding domain (RBD) of the spike protein and the nucleocapsid protein (N protein) of SARS-CoV-2 were investigated in maternal blood and umbilical cord blood from neonates. The study included 537 neonates and 565 mothers from the Faroe Islands, and follow-up samples were collected 12 months after birth. Multiple linear regression models were used to assess associations of maternal parameters with maternal and neonatal Ig levels and pregnancy outcomes. Results: The finding showed that neonates acquired varying levels of SARS-CoV-2 antibodies through transplacental transfer, and the levels were significantly influenced by the mother's vaccination and infection status. The study also found that maternal vaccination and the presence of SARS-CoV-2 antibodies targeting spike RBD were associated with gestational age and APGAR scores. Furthermore, the anti-RBD and -N protein-specific antibody response dynamics during 12 months after birth exhibited differences between mothers and children. RBD and N protein responses were maintained at follow-up in the mother's cohort, while only the N protein response was maintained at follow-up in the children's cohort. Conclusion: In conclusion, SARS-CoV-2-specific immune responses in newborns rely on maternal immunity, while the persistence of SARS-CoV-2-specific Igs appears to be differently regulated between mothers and children. The study provides new insights into the dynamics of SARS-CoV-2-specific immune responses in newborns and underscores the nuanced relationship between maternal factors and neonatal humoral responses. [ABSTRACT FROM AUTHOR]

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donorrecipient interactions, conditioning regimens, and inflammatory responses. Methods: This study investigated the role of the complement system during HSCT and its interaction with the cytokine network. Seventeen acute myeloid leukemia patients undergoing HSCT were monitored, including blood sampling from the start of the conditioning regimen until four weeks post-transplant. Clinical follow-up was 200 days. Results: Total complement functional activity was measured by WIELISA and the degree of complement activation by ELISA measurement of sC5b-9. Cytokine release was measured using a 27-multiplex immuno-assay. At all time-points during HSCT complement functional activity remained comparable to healthy controls. Complement activation was continuously stable except for two patients demonstrating increased activation, consistent with severe endotheliopathy and infections. In vitro experiments with post-HSCT whole blood challenged with Escherichia coli, revealed a hyperinflammatory cytokine response with increased TNF, IL-1b, IL-6 and IL-8 formation. Complement C3 inhibition markedly reduced the cytokine response induced by Staphylococcus aureus, Aspergillus fumigatus, and cholesterol crystals. Discussion: In conclusion, HSCT patients generally retained a fully functional complement system, whereas activation occurred in patients with severe complications. The complement-cytokine interaction indicates the potential for new complement-targeting therapeutic strategies in HSCT. [ABSTRACT FROM AUTHOR]

The lepirudin-based human whole blood model is a well-established ex vivo system to characterize inflammatory responses. However, the contribution of individual cell populations to cytokine release has not been investigated. Thus, we modified the model by selectively removing leukocyte subpopulations to elucidate their contribution to the inflammatory response. Lepirudin-anticoagulated whole blood was depleted from monocytes or granulocytes using StraightFrom Whole Blood MicroBeads. Reconstituted blood was incubated with Escherichia coli (108/mL) for 2 hours at 37 °C. CD11b, CD62P, and CD63 were detected by flow cytometry. Complement (C3bc, sC5b-9) and platelet activation (platelet factor 4, NAP-2) were measured by enzyme-linked immunosorbent assay. Cytokines were quantified by multiplex assay. A significant (P < 0.05) specific depletion of the monocyte (mean = 86%; 95% confidence interval = 71%–92%) and granulocyte (mean = 97%; 95% confidence interval = 96%–98%) population was obtained. Background activation induced by the depletion protocol was negligible for complement (C3bc and sC5b-9), leukocytes (CD11b), and platelets (NAP-2). Upon Escherichia coli incubation, release of 10 of the 24 cytokines was solely dependent on monocytes (interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-17A, interferon-γ, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein-1α, and fibroblast growth factor–basic), whereas 8 were dependent on both monocytes and granulocytes (IL-1ra, IL-6, IL-8, IL-9, IL-10, macrophage inflammatory protein-1β, tumor necrosis factor, and eotaxin). Six cytokines were not monocyte or granulocyte dependent, of which platelet-derived growth factor and RANTES were mainly platelet dependent. We document an effective model for selective depletion of leukocyte subpopulations from whole blood, without causing background activation, allowing in-depth cellular characterization. The results are in accordance with monocytes playing a major role in cytokine release and expand our knowledge of the significant role of granulocytes in the response to E. coli. By selective removal of leukocyte subtypes from human blood, we were able to use a holistic approach to identify cells responsible for the cytokine release induced by Escherichia coli incubated in the whole blood model. [ABSTRACT FROM AUTHOR]